The repair of osseous defects involves either non-resorbable or resorbable prosthetic structures. The resorbable structures or materials either support the in growth of adjacent bone and soft tissue or actively induce the formation of new bone. This active formation of new bone, termed osteoinduction, occurs only in the presence of demineralized bone matrix or in the presence of protein extracts from such matrix, or a combination of both materials. Particles or powders produced from demineralized bone matrix possess greater osteogenic potential per unit weight due to their increased surface area, than blocks or whole segments of demineralized bone.
Other methods of repairing damaged or missing osseous tissue or bone have also been explored. Replacement or support with nonresorbable materials, such as biocompatible metals, ceramics, or composite metal-ceramic materials, offers one method of clinical treatment. Some of these materials, such as metal grade titanium, can promote osteoinduction at their surface, thus leading to a stable, continuous interface with bone. Caffessee et al Journal of Periodontology, February 1987 utilizing a "window" implantation technique, established that nonabsorbable ceramics, such as hydroxyapatite, fail to stimulate tissue, even when placed in osseous defects. Resorbable ceramics, such as tricalcium phosphate, display better conduction of mineralized tissue into the resorbing graft material when placed in osseous defects. Unlike demineralized bone matrix, tricalcium phosphate or hydroxyapatite fail to stimulate induction of new bone when placed in non-osseous tissue. The addition of tricalcium phosphate or hydroxyapatite to demineralized bone matrix or to the extracted bone-inducing proteins actually inhibits the osteogenetic potential of these established osteoinductive compositions (see Yamazaki et al. Experimental Study On the Osteoindustion Ability of Calcium Phosphate Biomaterials with added bone Morphogenetic Protein Transations of the Society For Biomaterials pg 111, 1986.
Aside from the documented inability of hydroxyapatite and tricalcium phosphate ceramic materials to independently induce osteogenesis, recent clinical findings indicate that osteointegration of inorganic particles is highly dependent on the ability of those particles to remain fixed in a definite position, preferably near a bony interface. Hence, the immobility of the particles is a prerequisite for involvement with new bone formation (See Donath, et. al., A Histologic Evaluation of a Mandibular Cross Section One Year After Augmentation with Hydroxyapatite Particles Oral Surgery, Oral Medicine, Oral Pathology vol 63 No. 6 pp. 651-655, 1987
Nevertheless, numerous compositions have been derived to create clinically useful bone replacement materials. Cruz U.S. Pat. No. 3,767,437 describes artificial ivory or bone-like structures which are formed from a complex partial salt of collagen with a metal hydroxide and an ionizable acid, such as phosphoric acid. With regard to the metal hydroxide, this composition stresses the use of a polyvalent metal cation in the metal hydroxide, such as calcium hydroxide. Calcium phosphate may be added to the complex collagen salt. Cruz also recites the addition of fibers and ions to increase hardness and structural strength, but does not document or make claims with regard to these specific improvements. Cruz does not mention or claim these compositions to be osteoinductive or osteoconductive, nor does he mention their behavior in-vivo.
Thiele, et al., in U.S. Pat. No. 4,172,128, recites a process of degrading and regenerating bone and tooth material and products. This process involves first demineralizing bone or dentin, converting the demineralized material into a mucopolysaccharide-free colloidal solution by extraction with sodium hydroxide adding to the resultant solution a physiologically inert foreign mucopolysaccharide, gelling the solution, and then remineralizing the resulting gel. Thiele et al indicate this material to be biocompatible and totally resorbable, thus replaced by body tissue as determined by histiologic analysis the gel material produced by this process is reported to completely replace destroyed bone sections created in experimental animals. The patentees do not indicate any ability by the material to induce new bone. The ultimate fate of these materials in-vivo, or their ability to stimulate the formation of new bone in non-osseous implant sites is not described. The patentees do not describe or quantify the strength properties of these material. Nevertheless, since they are described as gels, one can assume their strength to be low.
Urist In U.S. No. Pat. No. 4,294,753, describes a process of extracting and solubilizing a Bone Morphogenetic Protein (BMP). This is a glycoprotein complex which induces the formation of endochrondral bone in osseous and non-osseous sites. This partially purified glycoprotein, which is derived from demineralized bone matrix by extraction, is lyophilized in the form of a powder. Urist describes the actual delivery of BMP in in-vivo testing via direct implantation of the powder, implantation of the powder contained within a diffusion chamber, or coprecipitation of the BMP with calcium phosphate. While Urist describes the induction of new bone after the implantation of one of these forms of BMP in either osseous or non-osseous sites, Urist fails to address the intrinsic physical strength properties of any of these delivery forms. Lyophilized powders and calcium phosphate precipitates, however, possess little if any, physical strength. Furthermore, more recent investigators (see aforementioned Yamazasaki, et al) indicate that calcium phosphate ceramics, such as tricalcium phosphate and hydroxyapatite, when present in high concentrations relative to the BMP present, may actually inhibit the osteogenic action of the BMP.
Jefferies in U.S. Pat. Nos. 4,394,370 and 4,472,840 describes bone graft materials composed of collagen and demineralized bone matrix, collagen and extracted Bone Morphogenetic Proteins (BMP). Also described is a combination of collagen, demineralized bone matrix, plus extracted bone morphogenetic proteins. Jefferies describes an anhydrous lyophilized sponge conjugate made from these compositions which when implanted in osseous and non-osseous sites, is able to induce the formation of new bone. The physical strength of these sponges is not specified in the disclosure, however, reports of the compressive strength of other collagen sponges indicates these materials to be very weak and easily compressible (much less then 1 kilogram load needed to affect significant physical strain in compression or tension).
Smestad in U.S. Pat. No. 4,430,760 assigned to Collagen Corporation, describes a nonstress-bearing implantable bone prosthesis consisting of demineralized bone or dentin placed within a collagen tube or container. As the patentee indicates, this bone prosthesis can not be used in stress-bearing locations clinically.
Glowacki et al., in U.S. Pat. No. 4,440,7550 apparently assigned to Collagen Corporation and Harvard University describe plastic dispersions of aqueous collagen mixed with demineralized bone particles for use in inducing bone in osseous defects. This graft material, as described exists in a gel state and possesses little physical strength of its own. Its use, therefore, must be restricted to defects which can maintain sufficient form and strength throughout the healing process. Furthermore, with time, the demineralized bone particle suspended within the aqueous collagen sol-gel begin to settle under gravitational forces, thus producing an nonhomogeneous or stratified graft material.
Seyedin, et. al., in U.S. Pat. No. 4,434,094, describes the purification of a protein factor, which is claimed to be different than Urist's BMP molecule, responsible for the induction of chondrogenic activity.
Bell, in U.S. Pat. No. 4,485,097, assigned to Massachusettes Institute of Technology, describes a bone equivalent, useful in the fabrication of prostheses, which is composed from a hydrated collagen lattice contracted by fibroblast cells and containing demineralized bone powder. As this prosthetic structure is also a hydrated collagen gel, it has little strength of its own. The patentee mentions the use of synthetic meshes to give support to the hydrated collagen lattices to allow handling. Nevertheless, there is no indication of the clinical use of the material or measurement of its total physical strength.
Ries, et. al., in U.S. Pat. No. 4,623,553, describes a method for producing a bone substitute material consisting of collagen and hydroxyapatite and partially crosslinked with a suitable crosslinking agent, such as glutaraldehyde or formaldehyde. The order of addition of these agents is such that the crosslinking agent is added to the aqueous collagen dispersion prior to the addition of the hydroxyapatite or calcium phosphate particulate material. The resultant dispersion is mixed and lyophilized. The patent lacks any well known components which are known osteogenic inducers, such as demineralized bone matrix or extracted bone proteins.
Caplan, et. al., in U.S. Pat. No. 4,620,327, describes a method for treating implants such as biodegradable masses, xenogenic bony implants, allografts, and prosthetic devices with soluble bone protein to enhance or stimulate new cartilage or bone formation. These structures may then be crosslinked to immobilize the soluble bone protein or retard its release. While the osteogenic activity of these implants are described in detail, their physical strength is not mentioned.
The above review of the prior art reveals that none of the bone prosthetic materials which claim the ability to induce new bone formation (osteoinductive materials) possess high strength characteristics. Furthermore, of those materials which are described with enhanced strength, these materials consist solely of a crosslinked conjugates of collagen and inorganic mineral, which lacks the ability to stimulate the induction of new bone.
It is especially relevant that none of the above references address the need to bind the dispersed particulate or inorganic phase to the organic carrier matrix (i.e. collagen). As will be described below, the treatment of demineralized bone matrix or particles or inorganic particles, prior to complexation with an organic biopolymer, such as collagen, is extremely important in determining the physical strength characteristics of the bioimplant.
Furthermore, the ability to orient protein or peptide particles in a stable fashion within organic or natural polymeric matrixes permits the ability to release drugs, bioactiveproteins, and bioactive peptides in a controlled fashion.